Abstract This application is in response to PA-18-591, NOT-AG-18-039. The proposed project expands our parent R01 grant, R01DC016065, from NIDCD. In the parent grant, we seek to study how the function of olfactory sensory neurons (OSNs) is regulated by a specific protein CFAP69 in mice. We propose extending two of the three Aims of our parent grant to include the study of OSNs in an Alzheimer's disease (AD) mouse model. Parent grant Aim 1 proposed characterizing in fine detail the altered electrophysiological response of OSNs in conditional Cfap69 mutant mice. In Supplement Aim 1, we will conduct comprehensive electrophysiological characterization of OSNs from an AD mouse model at three different time points (1.5 months, 7 months, and 12 months of age) representing different AD stages. These experiments will establish whether peripheral physiology defects may be associated with smell behavioral defects. Parent grant Aim 2 proposed using mass spectrometry-based proteomic approach to determine the molecular partners of CFAP69 protein from olfactory cilia in order to understand mechanisms underlying CFAP69 function. In Supplement Aim 2, we will extend these studies by conducting mass spectrometry and RNA-sequencing experiments on OSNs from the same AD mouse model at the same three time points in Supplemental Aim 1 to understand the major deviations in the proteome and transcriptome of these cells from that of healthy mice. This molecular characterization will form a basis for understanding the state and function of OSNs throughout AD. Given the time and workload constrain, we plan not to extend the third Aim, which addresses behavioral aspects of the mutant mice. We propose using the APP/PS1 mouse model, which is among the most commonly used mouse models in AD research and has well characterized brain pathologies and disease progression. Importantly, recent evidence in this mouse line indicates the olfactory epithelium (OE) may represent a point of origin for AD progression. Olfactory system defects, or even anosmia, are frequently the earliest symptom of AD in humans. The protein aggregates thought to be responsible in the brain for AD are also found in the OE, with OSN amyloid-? depositions appearing in more than 70% of AD patients. However, most previous studies using mouse models of AD have concentrated on the brain, and a detailed molecular and functional characterization of the OE throughout the course of AD development has yet to be conducted. The work proposed in the supplement aims to address this gap, and will lead to a better understanding of the impact of AD on OSNs, and vice versa, and will provide a reference for other mouse models. The proposed work falls well within the scope of the parent grant and are a natural extension of our expertise and research background. The proposed study will also lay the groundwork for future research in understanding of the causes of AD and in developing peripheral olfactory system-focused new methods of intervention or prevention.